Disease discovery and disease definition are critical first steps in elucidating pathogenetic mechanisms of cancer. Most insights into the molecular pathogenesis of lymphomas have followed on the heels of a precise elucidation of the disease entity based on clinical, pathological, or immunophenotypic grounds. Our work focuses on the definition of malignant lymphomas as tumors of the immune system, delineation of new disease entities, studies related to the pathophysiology of malignant lymphomas, and clinical correlations including prognosis and response to treatment. In July 2001, the WHO Classification of Tumours of the Hematopoietic and Lymphoid Tissues was published by the International Agency for Research on Cancer (IARC Press). This book culminated five years of work by more than 100 internationally recognized hematopathologists, hematologists and oncologists. This work reflects many of the contributions from our laboratory and others to define disease entities. It is a significant milestone, as it is the first classification of hematolymphoid neoplasia to receive worldwide acceptance. It is also a roadmap for future investigations, as it highlights areas requiring further investigation and study, such as diffuse large B-cell lymphomas and peripheral T-cell lymphomas. Our studies describing early events of lymph node involvement by follicular lymphoma (in situ follicular lymphoma) provide pathophysiological insights into mechanisms of pathogenesis and dissemination of the disease. Small numbers of neoplastic cells were shown to traffic and home to germinal centers. Our data suggest that in some patients without other evidence of disease the clonogenic event might take place in peripheral lymph nodes. Our studies to characterize T-cell malignancies have been extended. We described a syndrome affecting children of Asian and Hispanic descent associated with acute EBV infection, and leading to a fulminant T-cell lymphoproliferative disorder (LPD) and a concomitant hemophagocytic syndrome. This report identifies another EBV-associated neoplasm with a genetically linked predisposition in Asian and Hispanic patients. This racial profile is similar to that seen in extranodal NK/T-cell lymphoma, nasal type, and expands the profile of EBV-associated malignancies. In collaboration with Dr. Louis B. Staudt, we are defining the immunophenotypic and histological correlates of gene expression profiles, to extend this work to the routine diagnostic setting.